Using miniature swine inbred to homozygosity at the MHC loci, we have developed a large animal model of chronic lung allograft rejection that reproduces with fidelity those histologic lesions seen in patients suffering from chronic lung rejection. The current proposal is designed to elucidate the mechanisms of chronic lung allograft rejection in these swine, with particular attention to the role of indirect recognition of donor MHC peptides. We hypothesize that chronic lung rejection is an immunological process mediated by T cell recognition of alloantigens, and that indirect recognition of donor allopeptides may play a dominant role in this process. A recent clinical study demonstrated that allorecognition of HLA class I-derived peptides correlated with the development of chronic rejection in human lung transplant recipients. However, definitive experimental evidence linking indirect allorecognition and chronic rejection in the development of chronic lung rejection using synthetic class I MHC allopeptides Specifically, we will define which MHC peptides are recognized during chronic lung rejection and whether priming animals with immunogenic class I MHC peptides will induce or accelerate chronic lung rejection. Then, we will attempt to induce tolerance to the indirect pathway in lung transplant recipients using T cell co-stimulatory blockade combined with donor allopeptides. Our hypothesis would predict that this clinically relevant therapeutic strategy would prevent the development of chronic rejection. These preclinical studies will contribute substantially to our knowledge of the mechanisms and treatment of chronic lung rejection.